Blood lipoproteins such as low density lipoprotein (LDL) carry cholesterol into blood vessel walls where the cholesterol can accumulate causing atherosclerotic plaques. Massive accumulation of cholesterol by monocyte-derived macrophages (called foam cells) is a prominent feature of these atherosclerotic plaques. Because macrophages may trap or help remove lipoprotein cholesterol from lesions, it is important to understand the process by which these cells take up blood-derived lipoproteins such as LDL. LDL itself does not cause cholesterol accumulation within macrophages. However, much of the cholesterol that accumulates within atherosclerotic lesions occurs as cholesterol-rich liposomes having a greater than 2:1 unesterified cholesterol:phospholipid molar ratio. Previously, we showed that treatment of LDL with cholesterol esterase converts these 22-nm lipoprotein particles into 100-nm liposomes, similar to the liposomes in lesions. We have now learned that liposomes produced from cholesterol esterase-treated LDL are taken up by macrophages. Macrophage uptake of LDL-liposomes transforms the macrophages into foam cells following macrophage esterification of LDL-liposome unesterified cholesterol. LDL-liposomes did not enter macrophages by phagocytosis. Rather, the LDL liposomes induced and entered surface-connected compartments within the macrophages, a unique endocytic pathway in these cells. LDL-liposome apolipoprotein B (apo B) rather than LDL-liposome lipid mediated LDL-liposome uptake by macrophages. This was shown by the finding that protease treatment of the LDL-liposomes prevented macrophage cholesterol accumulation. Though apo B mediated the macrophage uptake of LDL-liposomes, this uptake did not occur through LDL, LRP, or scavenger receptors. Cholesterol esterase-mediated transformation of LDL into cholesterol-rich liposomes is an LDL modification that 1) stimulates uptake of LDL-cholesterol by apo B-dependent endocytosis into surface-connected compartments, and 2) causes human monocyte-macrophage foam cell formation. Next, learning under what conditions cholesterol esterase may be released from vascular cells such as macrophages will be important for determining what triggers the LDL-liposome pathway of foam cell formation.